Management of Bone Mineral Disorder in Dialysis Patients 2013. 4. 10 fellow 우성애

CKD-MBD Systemic disorder of mineral & bone metabolism due to CKD Abnormalities of Ca, P, PTH or Vit.D metabolism Abnormalities in bone turnover, mineralization, volume, linear growth, or strength Vascular or other soft tissue calcification

Pathogenesis Phosphate retention 1,25(OH)2D3 감소 Resistance of bone to PTH Ca sensor 감소 Klotho-FGFR1 Rc complex 감소 1,25(OH)2D3 receptors 감소 hypocalcemia hyperparathyroidism Renal function감소 FGF-23 Klotho 신기능이 감소함에 따라 신장에서 인배설이 감소하면서 혈청의 인 수치가 상승하게 됨. Serum P level은 GFR이 30이하로 감소할때까지 상승하지 않고 유지 – increased PTH 및 FGF(fibroblast growth factor)-23, P inself에 의해 tubular resorption이 감소

=> CKD 3부터 MBD에 대한 평가 및 조절필요 In mild to moderate CKD, a normal serum phosphate concentration does not necessarily indicate normal parathyroid status Efforts to control phosphate, including dietary phosphate restriction and the use of phosphate binders should not be delayed until frank hyperphosphatemia develops. => CKD 3부터 MBD에 대한 평가 및 조절필요 Ionized calcium and parathyroid hormone (PTH) levels in chronic renal failure.  Levels of ionized calcium are maintained in advancing renal failure by progressive increases in PTH

Hyperphosphatemia Control of phosphate is the cornerstone of effective management of secondary hyperparathyroidism

Phosphate Metabolism in Kidney Failure and in Health 정상인에서 혈청 인수치는 dietary absorption, bone formation and resorption, renal excreation의 regulation및 intracellular stores의 equilibration에 의해 physiologic range를 유지함. Kidney function이 저하됨에 따라 kidney의 인배설이 감소. 1) Dietary phosphorus restriction 2) Elimination of inorganic phosphate by dialysis 3) Phosphate binder <NEJM 2010;362:1312-24>

Dietary P restriction <IJKD 2010;4:89-100> KDOQI guidelines recommend up to 1000mg/d dietary P Inorganic P are not protein bound; they are salts that more readily disassociate and are absorbed in the intestinal tr. Turkey; 칠면조 <IJKD 2010;4:89-100>

치즈, 우유, 유제품, 두유, 아몬드,호두,달걀 노른자,돼지&소 간,초콜릿,콜라,사골국 달걀흰자, 닭다리, 닭가슴살, 대구 소고기&돼지고기(내장부위 제외) 두부 콩류 P to protein ratio < 5mg : egg white, pork rinds(돼지껍질 튀겨서 시원하게 먹는 스낵), orange roughy fish P to protein ratio 5~10; lamb, tuna/canned in water, chicken drumstick, beef(excludes organ meats), ground beef, chicken breast, pork(excludes organ meats). Cod fish 치즈, 우유, 유제품, 두유, 아몬드,호두,달걀 노른자,돼지&소 간,초콜릿,콜라,사골국 <KDOQI guideline>

Phosphate binder <comprehensive clinical nephrology>

Phosphate binder Aluminum containing(Amphojelⓡ) ~ mid 1980s, mainstay Systemic aluminum toxicity; encephalopathy, dementia, osteomalacia, anemia,GI side effects(esp. renal insufficiency) short period, 40-45mg/kg/d이하, Ca containing binder의 사용에 제한이 있 을때(hypercalcemia, extensive vascular calcification, calciphylaxis)

Ca based phosphate binders Taken with meals effectively binds phosphates and limits their absorption Doses may vary according to the patient’s compliance with dietary phosphate restriction as well as the CKD stage element Ca intake; max 1500mg/d(diet + binder; 2000mg/d미만) 문제점: hypercalcemia-associated risks including extraskeletal calcification and PTH suppression; adynamic bone disease > bone의 buffer capacity 감소하여 soft tissue Ca침착 증가, 심혈관 예후 악화 Avoid : bone turnover감소(PTH persistently low, <150), hypercalcemia(Ca >10.2), vascular calcification

Sevelamer Non-absorbable, Anion-exchange resin(칼슘, 금속 기반 아닌 인결합제) Sevelamer hydrochloride(renagelⓡ); metabolic acidosis sevelamer carbonate Ca based binder와 비교시 low Hypercalcemia incidence & vascular calcification,but mortality 차이없음 <"Treat-to-Goal" trial> Lower incidence of hypercalcemia (5 vs. 16%) Decreased incidence of low PTH levels (30 vs. 57%) Lower LDL-C (65 vs. 103 mg/dL) Much lower % increases in median absolute Ca- scores in coronary arteries (5 vs. 25%) & aorta (5 vs. 23%) <Kidney Int 2002;62:0245-252> Sevelamer may be combined c Ca containing binders if necessary 현재는 sevelamer carbonate가 FDA승인받고 생산, 효과는 비슷하고 산증 덜 일으킨다. 현재까지 study는 대부분 sevelamer hydrochloride로 이루어짐.

Lanthanum carbonate (Fosrenolⓡ) 금속 기반의 인결합제, sevelamer에 비해 적은양 복용, chewable cleared primarily by the liver some lanthanum appears to accumulate in bone and liver Expensive -sevelamer 800mg/1T 880원 > 2.4g/d복용시 79200원/mo -Lanthanum 500mg/1T 1270원 (CaCO3 500mg 1T 30원 > 1.5g(element Ca 600mg)/d 복용시 2700원/mo) 보험기준 투석을 받고 있는 ESRD 환자중 혈액검사상(매월 1회정도) 혈중 인(P) 수치가 5.5㎎/㎗ 이상이면서 Ca× P산물(product)이 55mg2/㎗2 이상인 환자에게 인정

calcium-containing phosphate binders remain a cost-effective first-line treatment option for the control of hyperphosphatemia, although the risk of long-term calcium exposure remains a concern. Limiting calcium-containing phosphate binder use persistent hyperphosphatemia even in combination with calcium-containing binders sevelamer may be most appropriate.

KDOQI & KDIGO guideline CKD 3-4 CKD5 Ca normal 8.4-9.5 mg/dL maintain normal range P 2.7-4.6 3.5-5.5 mg/dL towards normal range (dialysis) PTH 35-70 (CKD3) 70-110(CKD4) 150-300 pg/ml 2-9 times the upper limit of normal Ca x P <55 25(OH) VitD Not recommended in CKD stage 5 maintain within 30-100 ng/ml PTH 정상수치 8-76 Ca x P extraskeletal calcification의 risk factor로 알려져 있어 <55로 유지하도록 함. P을 정상수치로 유지해야 <55라는 목표에 도달할수 있음. Ca x P ; extraskeletal calcification의 risk factor

Ca P < 8.4 8.4 ≤ ~ < 9.5 9.5 ≤ ~ < 10.2 10.2≤ <3.5 CACA/CAAC식후1시간 No (CACA 쓰던경우 유지) (CACA 쓰던경우 감량) (CACA 쓰던경우 중지) 3.5≤ <5.5 5.5≤ <7.0 & Ca x P < 55 CACA/CAAC 3T with meal NO 5.5 ≤ <7.0 & Ca x P ≥ 55 Renagel 800mg tid & CACA/CAAC식후1시간 7.0 ≤ Renagel 1600mg tid Ca P <삼성 서울병원 가이드라인>

< 8.4 8.4 ≤ ~ < 9.5 9.5 ≤ ~ < 10.2 10.2≤ <3.5 3.5≤ <5.5 CACA/CAAC식후1시간 No (CACA 쓰던경우 유지) (CACA 쓰던경우 감량) 3.5≤ <5.5 5.5≤ <7.0 & Ca x P < 55 CACA/CAAC 3T with meal CACA/CAAC 3T with meal Ca x P ≥55 5.5 ≤ <7.0 7 ≤ Renagel 800mg tid Renagel 1600mg tid * 7 ≤ P & Ca x P < 55: Renagel 1600mg tid(비보험), aluminum based binder고려 Ca P >10.2시 Hypercalcemia <순천향 서울병원 가이드라인>

CaCO3; GI effect가 m/c A/E이지만, Sevelamer에서보다는 적다. <NEJM 2010;362:1312-24>

Treatment of abnormal PTH level

Secondary hyperparathyroidism VDRA(Vit D receptor activator) Calcimimetics parathyroidectomy

Vitamin D therapy Calcitriol(1,25-dihydroxyvitamin D),(Rocaltrolⓡ) Parathyroid gl의 the vitamin D receptor (VDR) 에 작용하여 PTH transcription을 억제, Parathyroid cell 증식 감소 뼈와 장에서 칼슘 흡수 증가시켜 혈청 칼슘을 증가 -> PTH분비 억제. Hypercalcemia, hyperphosphatemia, vascular calcification, adynamic bone dz Paricalcitol(19-nor-1-alpha,25-dihydroxyvitamin D2; Zemplarⓡ) "second generation" vitamin D analogue. Selective VDRA less severe increments in serum calcium and phosphate (prospective randomized trial is needed) Vitamin D derivatives should not be given until the serum phosphate con has been controlled (<5.5 mg/dL) and the serum calcium is less than 9.5 mg/dL : metastatic calcification risk (P <5.5 & Ca<9.5 가 아니라면 vitamin D 투여 금기) Calcitriol; activated form의 vitamin D Vitamin D analogue (paricalcitol, doxercalciferol, alfacalcidol) 인이 조절되지 않은 상태에서 hypercalcemia발생시 metastatic calcification risk가 증가함.

Calcimimetics acts as a positive allosteric modulator of the Ca sensing Rc(CaR) , increase the sensitivity of the CaR in the parathyroid gland to calcium Hypocalcemia and the calcium-sensing receptor — The CaSR, which is highly expressed in the parathyroid glands, permits variations in the serum calcium concentration to be sensed by the parathyroid gland, leading to the desired changes in PTH secretion. The fall in serum calcium concentration with renal failure, as sensed by the CaSR, is a potent stimulus to the release of PTH.

Calcimimetics Efficacy: Cinacalcet added to standard therapy facilitates the achievement of the Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines 56% vs 10% 46% vs 33% 42% vs 24% 41% vs 6% <Kidney Int. 2005;67(2):760>

Calcimimetics Cinacalcet(Regparaⓡ) Indication Dose patients with PTH >300pg/mL, sCa > 8.4mg/dL Dose Starting dose 30mg/d, stepwise increments to 60,90,180mg/d q 4wks should not be started if serum calcium is below 8.4 mg/dL